During the latest decades, much progression has been made in the suppression of acid secretion, an integral part of the treatment of dyspeptic disorders such as gastro-oesophageal reflux disease (GORD), duodenal and gastric ulcers and non-ulcer dyspepsia. Although the pathophysiology of these disorders is not identical, the inhibition of gastric acid secretion is pivotal to healing organic lesions, alleviating symptoms of discomfort and improving the quality of life. Moreover, acid-related damage may underlie the progression to cancers and other late complications of these conditions. Inhibition of acid secretion is also a cornerstone in the treatment regimens aiming for eradication of Helicobacter pylori infection.
Dyspepsia (acid dyspepsia) is a common disorder. Heartburn is a symptom of dyspepsia. It is estimated that 44% of Americans have heartburn at least once monthly but that only about 25% of them are seeing the doctor because of their dyspepsia problem. Symptoms associated with dyspepsia are for instance upper abdominal pain/discomfort and heartburn, indigestion, “sour” stomach, and gastro-esophageal reflux.
Dyspepsia is a multi-factorial disease and may be associated with organic pathology such as duodenal ulcer, gastric ulcer, esophagitis, Barrett's esophagus or gastro-duodenal inflammation (e.g., Helicobacter pylori infection). Dyspepsia also includes conditions where no organic pathology can be found, e.g., non-ulcer dyspepsia (NUD) or functional dyspepsia.
Dyspepsia can be controlled by administration of medicines that raise the pH in the stomach. Therapeutic agents effective in the treatment of dyspepsia include gastric acid suppressing agents, such as histamine H2 receptor antagonists (in the following called H2 receptor antagonists), acid susceptible proton pump inhibitors, antacids/alginates, anticholinergics and prokinetic agents. They can be distinguished by their mechanism of action, safety profile, and pharmacokinetics. The stomach pathogen Helicobacter pylori has been associated with dyspepsia, gastro-duodenal ulcer disease and stomach cancer. The treatment of H. pylori infection usually comprises the administration of a combination of acid secretion suppressing agents and one or two antibiotic agents.
The therapeutic effect on dyspepsia-related discomfort and organic lesions when inhibiting acid production by administration of acid secretion-inhibiting drugs is related to the degree of acid inhibition as well as to the onset and duration of action of the particular drug. The majority of patients who have symptomatic acid reflux disease have a normal esophageal mucosa or only a mild degree of oesophagitis. Treatment to relieve symptoms as they occur may be the best way to manage these patients, to whom the speed of symptom relief is of primary importance.
Antacid agents, that is, acid-neutralizing agents, and alginates are the first therapeutic choice in the treatment of mild heartburn. They have a extremely short duration of action but are seen as inexpensive and safe. Antacid agents work locally through a neutralization of gastric acid. Alginates provide some mechanical protection against reflux of gastric acid into the esophagus. The main advantages of antacid agents and alginates are that they provide fast relief of symptoms. The main disadvantage of antacid agents and alginates is their extremely short duration of action, and dosing has to be repeated frequently to keep the patients free of symptoms, further that antacids often do not provide symptom resolution, i.e. complete relief of symptoms. Moreover, these agents are not at all useful in the treatment of acid induced organic lesions, GORD or Helicobacter pylori infection.
Several classes of compounds are known which affect the secretion of gastric acid. Among them, acid susceptible proton pump inhibitors, such as the substituted benzimidazoles omeprazole, lanzoprazole, rabeprazole and pantoprazole and histamine H2 receptor antagonists, such as cimetidine, ranitidine and famotidine are the most prominent ones. H2 receptor and acid susceptible proton pump inhibitors are widely prescribed for reducing gastric acid secretion systemically.
The design of acid suppression therapy requires a detailed understanding of the mechanisms behind the secretion of hydrogen ions, namely the parietal cell and hydrogen-potassium adenosine triphosphate (H+,K+-ATPase) so that these mechanisms can be effectively targeted with pharmacological intervention. Three key factors have been identified in order to achieve an effective pharmacological treatment of acid related disorders (Dig Dis Sci 1995 vol 40: 24S-49S. Optimizing acid suppression for treatment of acid-related diseases.):
1) Time to onset of action, i.e. the inhibition of acid secretion should occur as rapidly as possible.
2) Degree of acid inhibition, i.e. the intragastric pH should be kept well above 4.
3) Duration of action, i.e. the inhibition of acid secretion should remain virtually complete during 24 hours on the first dose and remain complete during the course of treatment.
All of these factors must be considered when deciding how to optimize said suppressive therapy. However, several aspects of the parietal cell physiology and the pharmacology/biochemistry of existing pharmaceuticals have to date prevented the achievement of this goal.
Central to the acid secretory mechanism are the parietal cells of the stomach. These cells secrete hydrogen ions into the gastric lumen under the control of neurocrine, paracrine and endocrine pathways. One of the major paracrine factors is histamine released by the enterochromaffine-like (ECL) cells. The histamine released from the ECL cells stimulates parietal cells to acid secretion via histamin-2(H2) receptors located on the cell surface. Engagement of these receptors results in cyclic adenosine-3,5-monophosphate (cAMP) elevation and cAMP binding to the regulatory subunit. A variety of proteins will be phosphorylated, all of which will be relevant to activation of secretion. The molecular dissection of this intracellular pathway is far from complete, however, the action of cAMP includes translocation of H+,K+-ATPase into the secretory canaliculus and activation of the KCL transporters, i.e. put the parietal cell into a secretory state.
The first attempts of decreasing acid secretion targeted the paracrine pathway, namely the histamine H2 receptor activation-induced stimulation of acid secretion. Accordingly, the first class of acid inhibitors was the H2 receptor antagonists (H2 blockers), including compounds such as cimetidine, ranitidine, famotidine and nizatidine. Their mode of action is to antagonize the effects of histamine, i.e. to inhibit the recruitment of proton pumps to the secretory canaliculus and reduce the activity of KCL transport. This will put the parietal cells into a non-secretory state and thereby reduce the output of hydrogen ions (Dig Dis Sci 1995, vol 40:3S-23S. Pharmacological aspects of acid secretion).
However, phenomena of acid rebound and tolerance are major drawbacks to the use of these drugs in treating acid related diseases. There is an approximately 50% loss in acid reduction capacity during repeated dosing, which severely restricts the use of this class of drug in the treatment of, for example, GORD (Aliment Pharmacol Ther 1990, vol 4: 29-46. Tolerance during 29 days of conventional dosing with cimetidine, nizatidine, famotidine or ranitidine). Moreover, these agents are not at all useful in the treatment of Helicobacter pylori infection, a treatment dependent on an effective and sustained reduction of acid secretion.
Current treatment of acid related disorders is focused on a more direct target, the H+,K+-ATPase (“proton pump”) of the active parietal cell. These cells constitute the final acid sources—the acid secretory canaliculus and the acid pump itself. Therefore, drugs designed to inhibit acid secretion at this level show a greater efficacy and specificity. Because proton pump inhibitors (PPIs) act at a step downstream of the parietal cell stimulus, tolerance does not occur with the use of these compounds, in contrast to the H2 receptor antagonists. Moreover, these drugs hit the final target to which all other pathways converge, the H+,K+APPase in the acid space or canaliculus of the stimulated parietal cell.
Individual PPIs are similar with respect to their general structure, which consists of a substituted pyridylmethylsulfinyl benzimidazole. PKa values for these compounds vary from 4.0 to 5.0. All PPIs share the same pharmacological mechanism that is essentially the same: their pKa restricts accumulation of the compound to acid spaces, such as that in the parietal cell. PPI accumulation in the canaliculus of the parietal cell is followed by an acid-dependent activation step whereby the PPI is converted to sulphenic acid or sulphenamides. Formation of these reactive intermediates allows for binding to cysteine residues within the exposed luminal surface of the H+,K+-ATPase. The enzyme is functionally inactivated via the production of covalent disulphide bonds. The inhibition of H+,K+-ATPase by PPIs thus results in a relatively stable inhibition of the enzyme, as de novo synthesis of the enzyme is required to reverse the inhibition. These mechanisms of action is described in Dig Dis Sci 1995, vol 40:3S-23S. Pharmacological aspects of acid secretion.
One of the fundamental characteristics of the PPIs is that they are only functional in active parietal cells, i.e. the cells have to be in a secretory state. The reason for this is three-fold. Firstly, in most parietal cells, the acid space (canaliculus) has a pH of about 1.0. At this pH, the pKa values of PPIs allow them to accumulate in the parietal cell 1000- to 10,000-fold. However, at higher pH, for example 3, this accumulation decreases by two orders of magnitude, i.e. to 10- to 100-fold. Thus, the weak base characteristics of the PPIs allow them to accumulate only when acid is being formed by the parietal cell. This becomes important when administering PPIs during conditions when the parietal cell is put into a non-secretory state. Secondly, the conversion of PPI to sulphenic acid or sulphenamide is an acid-dependent process. Thirdly, the H+,K+-ATPase has to be activated, i.e. the enzyme has to be inserted into the membrane of the secretory canaliculus, where its cysteine residues can be reached by the sulphenamides (Pharmacotherapy 1997 vol 17:22-37. Proton pump inhibitors and acid related diseases; Drugs 1998 vol 56:307-335. Proton pump inhibitors: pharmacology and rationale for use in gastrointestinal disorders; Ann NY Acad Sci 1997 vol 834:65-76 Structural aspects of the gastric H+, K+-ATPase; Annu Rev Pharmacol Toxicol 1995 vol 35:277-305. The pharmacology of the gastric acid pump).
These characteristics of the pharmacology/biochemistry of the PPIs will profoundly affect the pharmacodynamics of this class of compounds. On one hand, these drugs require an active enzyme for inhibition and some pumps are not active while the drug is present in the blood. On the other hand, the PPIs exhibit a relatively short plasma half-life of 60 minutes, and new pumps are synthesized at a rate of 25% per 24 hours.
These facts point to the therapeutic dilemma of PPIs at present. As the compounds are accumulated and converted in the acidic space of the parietal cell, only those pumps which are secreting acid will be inhibited. Since the cell has a reserve of inactive pumps and is in the process of synthesizing new pumps, many pumps destined to be active within the next 24 hours will not be inhibited by the first dose. However, the following day, when PPI is given again, new pumps have been recruited and can be inhibited, and the pumps inhibited 24 hours previously have not been replenished entirely. Therefore, the response to PPIs is cumulative, reaching a steady state and therapeutic acid inhibition first after at least three consecutive days of treatment.
Thus, the current concept regarding PPIs mechanisms of action is the need for active pumps to mediate their effects. In the resting state, parietal cells produce no acid and the pumps are inactive. The inhibition of acid production by PPIs occurs when these pumps are in the active state, via accumulation in the parietal cell, such that subsequent activation of the drug results in an inhibition of the pump (Eur J of Gastroentereol Hepatol 2001 vol 13:S35-S41. Improving on PPI-based therapy of GORD)
In summary, neither class of anti-secretory drugs available today attain the goal for acid control stated above, i.e. of a rapid onset of action, potent inhibition of acid secretion and a sustained duration of action during the course of treatment. This goal is of the utmost importance for the clinical outcome of treatment, as the therapeutic effect is related to the onset, degree and duration of action, i.e. how quickly, how much and for how long the pH is raised in the stomach.
Various combinations of antacid and/or mucosa-protecting agents with agents that reduce acid secretion have been disclosed to be useful in treating dyspepsia.
WO 95/01708 describes a composition for use in the treatment of for instance heartburn comprising an H2 receptor antagonist, such as famotidine, and an alginate and optionally simethicone (an activated polysiloxane).
EP 338861 A describes a solid pharmaceutical preparation consisting of an antacid and excipients which is proposed to be used in combination with an acid-susceptible proton pump inhibitor or any other substance inhibiting gastric acid secretion. There is no suggestion to combine these substances in a fixed unit dosage form.
U.S. Pat. No. 5,244,670 A describes an ingestible pharmaceutical composition comprising a substance selected from the group consisting of antacid agents, acid secretion-prevention agents, bismuth-containing agents and their mixtures, and 3-(1-menthoxy)-propane-1,2-diol which is present to provide a cooling sensation to the throat.
WO 97/25066 discloses a pharmaceutical formulation comprising a combination of an acid-susceptible proton pump inhibitor or an H2 receptor antagonist and one or more antacid agents or alginates.
Neither acid-susceptible proton pump inhibitors nor H2 receptor antagonists, alone or in combination with antacids and/or alginates, provide fully satisfactory quick and lasting relief to patients, to whom the speed of symptom relief is of primary importance but who also desire to be free of symptoms for a longer period of time. Thus, none of the solid pharmaceutical preparations for per-oral administration reported to date, satisfies the basic requirements; rapid onset of acid secretion inhibition, potent reduction of acid secretion and a sustained inhibition of acid secretion.
Furthermore, the use of proton pump inhibitors has a serious shortcoming regarding chemical stability:
The substances are extremely acid-labile, which has made special formulations necessary. Normally, the substances are protected in vivo by the application of a gastric acid-resistant coating (enteric coating) over the active substance. As such coatings in themselves are acidic (release hydrogen ions), it has been found that it is also necessary to provide some sort of protection in vitro, i.e. when the product is stored.
This protection in vitro may be arranged such as is described in U.S. Pat. No. 6,183,776 B1 (Depui et al.), where an alkaline-reacting substance is added together with the proton pump inhibitor, and a supplementary protective coating (sub-coat) is applied just under the gastric acid-resistant coating.
Another approach is disclosed in WO 00/78284 (U.S. Pat. No. 5,225,202), where the gastric acid-resistant coating is neutralized such that it shows no acid reaction during storage. After swallowing, the hydrogen ions present in the stomach will acidify the coating and thus recreate the acid-protecting properties of the coating in situ.
It has now been found that both the problem regarding rapid and long lasting relief of symptoms as well as the chemical instability problem of acid succeptible proton pump inhibitors may be solved by the present invention.